We are studying cell regulation by signaling in the Drosophila system. The powerful genetic tools, in combination with excellent cytological markers available in the Drosophila system, make it an excellent model to address cell biology problems.We are focusing on the JAK/STAT and JNK/JUN signal transduction pathways. The JNK/JUN pathway regulates epithelial cell sheet movement and wound healing in Drosophila. The JAK/STAT pathway regulates various developmental processes in Drosophila, including sex determination, male germline stem cell self-renewal, border cell migration female ovary, and fly innate immunity. Furthermore, hyperactivation of the JAK/STAT pathway leads to melanotic tumor formation in the fly. In the last few years, we have concentrated on identifying components of the signal transduction pathways to understand the signal transduction mechanism. Our achievements include identification of a receptor for the JAK/STAT signal transduction pathway (Chen et al., Genes Dev. 16: 388-398, 2002) and characterization of Cyclin D/Cdk4 regulating STAT protein stability (Chen et al., Dev Cell 4:179-190, 2003). We further demonstrated that the JAK/STAT pathway and Cyclin D/Cdk4 cooperatively regulate "tumor-like" outgrowth in the fly eye. Our first objective in the next few years will be to understand how the JAK/STAT pathway and cell cycle regulators cooperatively regulate tissue outgrowth. One of the hallmarks of cancer is the loss of normal growth control. This genetic system provides an opportunity to gain new insight into this fundamental cancer cell biology problem.In the JNK/JUN signal transduction pathway, our achievements include characterization of a new gene connector of kinase to AP-1 (cka), which encodes a multidoman scaffolding protein of the JNK/JUN signal transduction pathway (Chen et al., Mol. Cell. Biol. 22:1792-1803, 2002). This pathway regulates epithelial cell sheet movement and wound healing in Drosophila. Mutations that disrupt the signaling result in a hole on the dorsal side of the embryo, so-called "dorsal open" (DO) phenotype. We have screened and identified 38 new DO mutations in the last few years. One of these mutations disrupted a novel small GTPase guanine nucleotide exchange factor (NGEF). The epithelial cell sheet does not move, due to the disruption of cell polarity in the NGEF mutant. Several apical proteins are found basally and laterally as well as apically in the mutant. Further, when we generated GFP-marked NGEF mutant mosaic clones in the fly wing imaginal disc, many GFP-marked mutant cells invaded into surrounding wild-type tissues. Cell invasion is another poorly understood cell biology problem and also a hallmark of later stage tumors. Our second objective is to gain new insight into cell invasion through studying the NGEF mutation.